A novel antimycobacterial compound acts as an intracellular iron chelator. Academic Article uri icon


  • Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.

published proceedings

  • Antimicrob Agents Chemother

altmetric score

  • 8.008

author list (cited authors)

  • Dragset, M. S., Poce, G., Alfonso, S., Padilla-Benavides, T., Ioerger, T. R., Kaneko, T., ... Rubin, E. J.

citation count

  • 27

complete list of authors

  • Dragset, Marte S||Poce, Giovanna||Alfonso, Salvatore||Padilla-Benavides, Teresita||Ioerger, Thomas R||Kaneko, Takushi||Sacchettini, James C||Biava, Mariangela||Parish, Tanya||Argüello, José M||Steigedal, Magnus||Rubin, Eric J

publication date

  • April 2015